Abstract

3673

High circulating levels of Insulin-like growth factor binding protein-1 (IGFBP-1) have been associated with a reduced risk of colorectal cancer. Elevated IGF binding protein-3 (IGFBP-3) levels have been associated with a reduced risk of prostate cancer and an increased risk of premenopausal breast cancer. Approximately 40% and 60% of the variation in circulating levels of IGFBP-1 and IGFBP-3, respectively, are attributed to genetic effects, yet the specific genomic regions influencing the levels of these proteins in the circulation have not been identified. We conducted a cross-sectional study to investigate whether common genetic variation at the IGFBP1/IGFBP3 loci are associated with variation in circulating levels of IGFBP-1 and IGFBP-3 among African-American, Hawaiian, Japanese-American, Latino, and White men and women in the Multiethnic Cohort (MEC). Plasma levels of IGFBP-1 and IGBFP-3 were measured in a random sample of 1,000 MEC participants (n=100 controls for each racial/ethnic group by sex). To characterize the genetic variation of IGFBP1/IGFBP3, 36 densely spaced single nucleotide polymorphisms (SNPs) (1 every ∼2.0 kb) spanning 71 kb of the IGFBP1/IGFBP3 loci were genotyped in a multiethnic panel (n=69-70 per racial/ethnic group). A subset of 24 SNPs were then selected to effectively capture the common (>5% frequency) genetic variation of IGFBP1/IGFBP3. Analysis of covariance was used to evaluate the influence of IGFBP1/IGFBP3 genotypes/haplotypes on levels of IGFBP-1 and IGFBP-3. Analyses were conducted on 928 MEC subjects with complete IGFBP-1 and IGFBP-3 measurements adjusting for age, racial/ethnic group, and sex. In preliminary analysis, we observed a nominally significant positive association between an IGFBP1 haplotype in the African-American population, haplotype 1G, and levels of IGFBP-1 in the circulation (P trend = 0.03). The SNP4 (rs2201638) G allele was nominally significantly associated with higher IGFBP-1 levels (P trend = 0.03) and explained approximately 11% of the variation in levels. This G allele did not specifically mark the African-American 1G haplotype. We also observed a nominally significant association (P trend < .0001) between the IGFBP-3 (A-202C) polymorphism and circulating IGFBP-3 levels. The presence of the A allele was associated with higher IGFBP-3 levels and accounted for 10% of the variation in IGFBP-3 levels. Currently, we are completing our haplotype analysis of the IGFBP3 locus. Future work will examine whether dietary and lifestyle determinants in combination with common genetic variation in IGFBP1/IGFBP3 influence levels of IGFBP-1 and IGFBP-3 in the circulation. Overall, genetic variation in IGFBP1 and IGFBP3 do not appear to substantially influence IGFBP-1 and IGFBP-3 levels, and trans-acting variants at other loci are likely to exist and control circulating levels in vivo.